The success of artemisinin-based combination therapies in combating Plasmodium falciparum malaria has inspired calls for the eradication of this devastating parasitic disease. However, new reports of emerging artemisinin resistance, and the absence of alternative first-line drugs, highlight an urgent need for new control methods. We propose a bold new plan to develop a new generation of antimalarial vaccines and drugs using a multidisciplinary, collaborative approach to exploit one particular biochemical pathway in the parasite lifecycle. Most currently available antimalarials target the symptomatic blood stage parasites rather than the initial asymptomatic liver stage, while many vaccine efforts have focused on recombinant subunit-based approaches. We are proposing a completely different approach based on our recent discovery that liver and blood stage parasites differ fundamentally in their fatty acid biology. In the rodent parasite P. berghei, deletion of the fabI gene, involved in de novo type II fatty acid synthesis (FAS-II), had no measurable effect on blood stage parasite growth, indicating that this stage depends on the import and modification of host fatty acids for intracellular replication. In contrast, the disruption of the fabI gene severely compromised the ability of the liver stage parasites to complete their development and initiate blood stage infection. In the related rodent species P. yoelii, deletion of the FAS-II gene fabB/F produced parasites that never completed their liver stage development. These attenuated parasites elicited robust protective immunity against infectious parasite challenge. Based on these findings, we hypothesize that parasite stage-specific differences in fatty acid metabolism can be uniquely exploited to develop effective antimalarial vaccines and drugs. We will implement a systematic approach to identifying combinations of genes involved in fatty acid metabolism and related processes, which when deleted can cause a total arrest of parasite liver stage development and elicit a robust and fully protective immune response. Successful P. berghei vaccines will be translated into P. falciparum to initiate preclinical assessments, in collaboration with Sanaria. We also define an experimental approach to evaluate a panel of FAS-II inhibitors, available from GlaxoSmithKline, for their ability to block liver stage development in vitro and in vivo. If potent and pharmacologically suitable inhibitors are found, these will be evaluated in a primate malaria prophylaxis model. Finally, our investigations of parasite mechanisms of import and modification of host fatty acids during asexual blood stage replication will validate the key effectors and guide the development of screens for curative agents that kill Plasmodium blood stages by starving them of essential host nutrients. This "high risk/high reward" project is based on a collaborative effort between academic groups and industry partners that can rapidly translate experimental discoveries into preclinical assessment. The successful discovery of new interventional tools arising from this project has the exciting potential to fundamentally transform the way in which malaria is prevented and controlled. ) PUBLIC HEALTH RELEVANCE: This Transformative R01 application proposes an entirely novel approach to developing vaccines and drugs to prevent malaria, based on our recent discovery of a fundamental difference in the way parasites replicating at the liver versus the blood stage acquire their fatty acids during intracellular growth. Exploiting the dependency of fatty acid synthesis by liver stage parasites, we propose to develop fatty acid synthesis-deficient, genetically attenuated parasite vaccines that arrest in the liver, causing a host immune response that protects against infectious challenge. In addition, we propose to target parasite synthesis as well as salvage of host fatty acids, as a means to develop novel prophylactic and curative medicines that can prevent and control this widespread and devastating disease.